Targeting NADPH Oxidase in Inflammation-Promoted Pancreatic Tumorigenesis
Abstract
This proposal addresses the Fiscal Year 2019 Peer Reviewed Cancer Research Program Topic Areas of pancreatic cancer, with a Focus Area of gaps in the prevention and treatment of pancreatic cancer in association with inflammation incurred by microbial infections and overweight/obesity that prevail in the military. The scientific objective of the proposed studies is to understand how inflammation contributes to pancreatic cancer, which remains an outstanding knowledge gap as well as an obstacle in identifying critical new targets for pancreatic cancer therapy. Pancreatic cancer is a highly lethal disease and is projected to become the second-leading cause of cancer-related deaths in the United States. Military and Veteran populations are at an even greater risk of developing this devastating malignancy, owing to the prevalent inflammatory problems as a result of a higher frequency of exposure than civilians to hazardous wild-field environments, dangerous deployments, dietary challenges, wounds, and post-traumatic stress as the nature of their Service. As such, Service members are particularly vulnerable to environmental microbial infections that evoke a serious inflammatory response. The incidence of overweight and obesity of multiple causes that entails a low yet chronic metabolic inflammatory state is also skyrocketing and becoming a huge problem in the U.S. military. Mounting epidemiological, experimental, and clinical evidence suggests that inflammation conspires with oncogenic KRAS, which dominates in 95% patients, to promote aggressive pancreatic ductal adenocarcinoma (PDAC), the predominant form of pancreatic cancer. At the molecular level, pancreatic inflammation was found to enhance mutant KRAS activity to accelerate pancreatic tumorigenesis. However, the identity of the key molecule and related pathway that dictate such cooperative interaction remains elusive. Lack of this information has become a bottleneck of field progress and therapeutic advancement. Inflammation is known to activate reactive oxygen species (ROS)-generating NADPH oxidase (NOX), while oncogenic KRAS also mainly activates NOX to increase ROS levels and oxidative stress in cancers. ROS is known to modify the redox-sensitive NKC118D motif of wild-type KRAS, leading to transient activation. Unfortunately, such modification has not been investigated as a potential mechanism by which chronic inflammation promotes the observed hyperactivation of mutant KRAS, which in turn amplifies aberrant oncogenic signaling. We propose that ROS-generating NOX works in close liaison with ROS modification of mutant KRAS, leading to the formation of a co-activation partnership between NOX and oncogenic KRAS to drive pancreatic tumorigenesis. Specifically, we will examine (1) the roles of NOX as a key molecular mediator of inflammation-promoted mutant KRAS hyperactivation to drive invasive PDAC, and (2) the roles of the redox-sensitive NKC118D motif in mediating mutant KRAS hyperactivation under inflammation. To achieve this, we will employ novel inducible mouse models in which NOX or the redox-sensitive NKC118D motif of mutant KRAS are inactivated in mutant KRAS expressing mice. These mice will be challenged with bacteria-derived lipopolysaccharides toxin or obesogenic high-fat diet, which recapitulates the effect of microbial infections and obesity, respectively. This study will unveil a new facet of biology in oncogenic KRAS activation, a new direction in understanding tumorigenesis, and thus, fill the outstanding knowledge gap of how inflammation fosters a milieu for advancing pancreatic cancer with molecular details. In the longer-term, defining the potentially vital circuitry of NOX, ROS, redox modification, and oncogenic KRAS, which act synergistically in a feed-forward fashion, will open new avenues in pursuing novel targets for the challenging and unmet clinical needs in pancreatic cancer and will ultimately benefit at-risk active duty Service member, V
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010625
Entities
People
- Weiqin Lu
Organizations
- Stony Brook University
- United States Army